Tadashi Imafuku1,2, Hiroshi Watanabe1, Takao Satoh3, Takashi Matsuzaka4,5, Tomoaki Inazumi6, Hiromasa Kato1, Shoma Tanaka1, Yuka Nakamura1, Takehiro Nakano1, Kai Tokumaru1, Hitoshi Maeda1, Ayumi Mukunoki7, Toru Takeo7, Naomi Nakagata7, Motoko Tanaka8, Kazutaka Matsushita8, Soken Tsuchiya6, Yukihiko Sugimoto6, Hitoshi Shimano4,9, Masafumi Fukagawa10, Toru Maruyama1. 1. Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan. 2. Program for Leading Graduate Schools "HIGO (Health Life Science: Interdisciplinary and Glocal Oriented) Program," Kumamoto University, Kumamoto, Japan. 3. Kumamoto Industrial Research Institute, Kumamoto, Japan. 4. Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, Japan. 5. Transborder Medical Research Center, University of Tsukuba, Ibaraki, Japan. 6. Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan. 7. Division of Reproductive Engineering, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan. 8. Department of Nephrology, Akebono Clinic, Kumamoto, Japan. 9. Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology, Tokyo, Japan. 10. Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Kanagawa, Japan.
Abstract
Background: Renal proximal tubulopathy plays a crucial role in kidney disease, but its molecular mechanism is incompletely understood. Because proximal tubular cells consume a lot of energy during reabsorption, the relationship between fatty acids (FAs) and proximal tubulopathy has been attracting attention. The purpose of this study is to investigate the association between change in renal FA composition and tubulopathy. Methods: Mice with cisplatin-induced nephrotoxicity were used as a model of AKI and 5/6-nephrectomized mice were used as a model of CKD. Renal FA composition in mice was measured by GC-MS. Human tubular epithelial cells (HK-2 cells) were used for in vitro studies. Results: In kidneys of AKI mice, increased stearic acid (C18:0) and decreased palmitic acid (C16:0) were observed, accompanied by increased expression of the long-chain FA elongase Elovl6. Similar results were also obtained in CKD mice. We show that C18:0 has higher tubular toxicity than C16:0 via induction of ER stress. Using adenovirus-expressing Elovl6 or siRNA for Elovl6 in HK-2 cells, we demonstrated that increased Elovl6 expression contributes to tubulopathy via increasing C18:0. Elovl6 knockout suppressed the increased serum creatinine levels, renal ER stress, and inflammation that would usually result after 5/6 nephrectomy. Advanced oxidation protein products (AOPPs), specifically an oxidized albumin, was found to induce Elovl6 via the mTORC1/SREBP1 pathway. Conclusions: AOPPs may contribute to renal tubulopathy via perturbation of renal FAs through induction of Elovl6. The perturbation of renal FAs induced by the AOPPs-Elovl6 system could be a potential target for the treatment of tubulopathy.
Background: Renal proximal tubulopathy plays a crucial role in kidney disease, but its molecular mechanism is incompletely understood. Because proximal tubular cells consume a lot of energy during reabsorption, the relationship between fatty acids (FAs) and proximal tubulopathy has been attracting attention. The purpose of this study is to investigate the association between change in renal FA composition and tubulopathy. Methods: Mice with cisplatin-induced nephrotoxicity were used as a model of AKI and 5/6-nephrectomized mice were used as a model of CKD. Renal FA composition in mice was measured by GC-MS. Human tubular epithelial cells (HK-2 cells) were used for in vitro studies. Results: In kidneys of AKI mice, increased stearic acid (C18:0) and decreased palmitic acid (C16:0) were observed, accompanied by increased expression of the long-chain FA elongase Elovl6. Similar results were also obtained in CKD mice. We show that C18:0 has higher tubular toxicity than C16:0 via induction of ER stress. Using adenovirus-expressing Elovl6 or siRNA for Elovl6 in HK-2 cells, we demonstrated that increased Elovl6 expression contributes to tubulopathy via increasing C18:0. Elovl6 knockout suppressed the increased serum creatinine levels, renal ER stress, and inflammation that would usually result after 5/6 nephrectomy. Advanced oxidation protein products (AOPPs), specifically an oxidized albumin, was found to induce Elovl6 via the mTORC1/SREBP1 pathway. Conclusions: AOPPs may contribute to renal tubulopathy via perturbation of renal FAs through induction of Elovl6. The perturbation of renal FAs induced by the AOPPs-Elovl6 system could be a potential target for the treatment of tubulopathy.
Authors: Yumiko Oishi; Nathanael J Spann; Verena M Link; Evan D Muse; Tobias Strid; Chantle Edillor; Matthew J Kolar; Takashi Matsuzaka; Sumio Hayakawa; Jenhan Tao; Minna U Kaikkonen; Aaron F Carlin; Michael T Lam; Ichiro Manabe; Hitoshi Shimano; Alan Saghatelian; Christopher K Glass Journal: Cell Metab Date: 2016-12-29 Impact factor: 27.287
Authors: Mustafa Arici; Ravinder Chana; Andrew Lewington; Jez Brown; Nigel John Brunskill Journal: J Am Soc Nephrol Date: 2003-01 Impact factor: 10.121